I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation.
A decrease in orexin-A (OX-A) levels has been reported to be associated with depression. It is also well known that stress and depression can disrupt neurogenesis in the dentate gyrus of the hippocampus; however, it is unclear how OX-A is involved in depression and/or neurogenesis. In the present study, we investigated the effect of i.c.v. administration of OX-A on the forced swimming test (FST), an accepted behavioral screen of antidepressant-like activity, and on the cell proliferation with bromodeoxyuridine (BrdU) in the dentate gyrus at 4 days after i.c.v. administration of OX-A. OX-A administration (140 pmol/mouse) led to a significant reduction in animal immobility in the FST, without affecting spontaneous locomotor activities or serum corticosterone levels. In addition, the number of BrdU-positive cells in the dentate gyrus was significantly increased in OX-A-treated mice in vivo; however, OX-A did not affect the percentage of doublecortin-positive cells in the dentate gyrus. The proliferation of neural progenitor cells derived from rat fetal brain was not affected by OX-A treatment in vitro, and the orexin receptor 1 (OXR1) protein was not expressed in these cells. Treatment with the OXR1 antagonist SB-334867 (30 mg/kg, i.p.) blocked both the OX-A-induced decrease in the immobility of FST and increase in BrdU-positive. Moreover, the OX-A-induced increase in neuropeptide Y (NPY)-positive cells in the hilus of the dentate gyrus was blocked by SB-334867. These results suggest that OX-A induces an antidepressive-like effect, at least in part, via the enhancement of cell proliferation in the dentate gyrus. These effects of OX-A also may be partly relevant to the regulation of the NPY system in the hilus of the dentate gyrus.
Ito
N
N
Oriental Medicine Research Center, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, Japan.
Yabe
T
T
Gamo
Y
Y
Nagai
T
T
Oikawa
T
T
Yamada
H
H
Hanawa
T
T
D000704:Analysis of Variance; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000089662:Doublecortin Protein; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D046353:Immobility Response, Tonic / Q000187:drug effects; D007276:Injections, Intraventricular / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009287:Naphthyridines; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000008:administration & dosage*; D018377:Neurotransmitter Agents / Q000008:administration & dosage*; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea; D001973:Bromodeoxyuridine